Depression and anxiety disorders are large health burdens to our society with reported yearly prevalence rates of 9-18% in the general population. Although women are twice as likely to suffer from depression or anxiety, and exhibit more severe symptoms, the great majority of studies at the basic science level have used only male rodents to determine the underlying biological mechanisms. As a consequence, there is far less known about the mechanisms of depression in females. Here we use the chronic variable stress (CVS) paradigm, a model that induces robust depression- and anxiety-like behavior in mice. Our findings show that females are more sensitive to CVS than males on 5 established depression and anxiety behavioral and neurochemical domains. For example, females exhibit greater immobility on the forced swim test (FST), anhedonic responses on sucrose preference tests (SPT), decreased time grooming on the splash test, increased latency to feed on novelty suppressed feeding (NSF), and increased serum corticosterone levels. Although the direct mechanisms driving these sex differences are unclear, we used RNA sequencing and found that there are approximately 800 genes regulated by CVS in males and females and less than 3% of them overlap. Interestingly, CVS regulates more genes in males than females, suggesting that the lack of behavioral response in males may not be a passive one. Rather, males may engage alternate transcriptional pathways providing a mechanism for acting coping. In this application, we will measure the detailed sex differences in stress-induced changes across the transcriptome using high resolution paired end RNA sequencing and advanced bioinformatics analysis to identify splicing events, alternative promoter usage and microRNA processing. All data sets will be further analyzed into functional biological clusters to determine sex differences in the major pathways regulated by stress. We believe that this work will provide an enormously important resource of information for future stress studies and initiate a program to test the functional relevance of these transcriptome differences. The latter will aide in the development of new personalized anti- anxiety and anti-depression therapeutic strategies.